Determination of the second-order 1H NMR parameters for the aromatic protons in 4-fluoroaniline and application to the analysis of the 1H NMR spectra for the aromatic protons in N4-(4′- fluorophenyl)succinamic acid and in

Article abstract of DOI:10.1016/j.jfluchem.2011.02.003

Four studies of the ¹H NMR spectrum for the aromatic protons of 4-fluoroaniline between 1958 and 1974 give three very different solutions to the second-order, AA′BB′X, spectrum. A re-evaluation of the second-order spectrum was done at 300 MHz.

Full text of DOI:10.1016/j.jfluchem.2011.02.003

Journal of Fluorine Chemistry 132 (2011) 269–275
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
1
Determination of the second-order H NMR parameters for the aromatic
1
protons in 4-fluoroaniline and application to the analysis of the H NMR
spectra for the aromatic protons in N4-(40-fluorophenyl)succinamic acid
and in N4-(40-fluorophenyl)-3,3-difluorosuccinamic acid
*
John M. Risley , John P. Kastanis, Amber M. Young
Department of Chemistry, The University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC 28223-0001, United States
A R T I C L E I N F O
A B S T R A C T
Four studies of the 1H NMR spectrum for the aromatic protons of 4-fluoroaniline between 1958 and 1974
give three very different solutions to the second-order, AA0BB0X, spectrum. A re-evaluation of the second-
order spectrum was done at 300 MHz. Simultaneous simulations of the 1H NMR spectrum and 19F NMR
spectrum for 4-fluoroaniline were done using WINDNMR-Pro, and a new set of parameters for the six
coupling constants was obtained from the optimized simulations. This new set of parameters was used
as a basis to evaluate the AA0BB0X spectrum for the aromatic protons in N4-(40-fluorophenyl)succinamic
acid and in N4-(40-fluorophenyl)-3,3-difluorosuccinamic acid by simultaneous simulations of the 1H
NMR spectrum and 19F NMR spectrum for each using WINDNMR-Pro. Formation of the amide bond
results in small, but significant, changes in the values for the set of parameters in both molecules. These
results confirm that second-order analyses as an AA0BB0X system are required for derivatives of 4-
fluoroaniline, rather than first-order analyses that have been used in previous reports.
Article history:
Received 31 December 2010
Received in revised form 31 January 2011
Accepted 1 February 2011
Available online 1 March 2011
Keywords:
4-Fluoroaniline
1H NMR spectroscopy
19F NMR spectroscopy
Second-order AA0BB0X system
WINDNMR-Pro NMR simulation
Succinamic acid anilide
ß 2011 Elsevier B.V. All rights reserved.
1. Introduction
ophenyl)succinamic acid (2) [5,6], and we wished to compare the
1H NMR spectrum for the aromatic protons of 4-fluoroaniline with
The 1H and 19F NMR spectra for the aromatic protons of 4-
fluoroaniline (1) form a second-order, AA0BB0X system; the 1H NMR
spectrum is the AA0BB0 part of the system and the 19F NMR
spectrum is the X part of the system. The amino protons are a broad
singlet with no interaction with the aromatic protons or fluoro
group. An analysis of the AA0BB0X spectrum was reported, first, at
29.92 MHz (neat) [1]. Subsequently, analyses at 40 MHz (in CCl4)
[2], 60 MHz (neat) [3], and 250 MHz (in CDCl3 in the presence of a
lanthanide shift reagent) [4] were reported. When the results from
these four analyses are used to simulate the NMR spectrum for the
aromatic protons of 4-fluoroaniline at 300 MHz, three very
different spectra are obtained. With the significant improvements
in NMR instrumentation that have been made since the last
reported analysis in 1974, we investigated the 1H NMR spectrum
and 19F NMR spectrum for the aromatic protons of 4-fluoroaniline.
We needed this information because, in our continuing study of the
mechanism of glycosylasparaginase, we synthesized N4-(40-fluor-
the H NMR spectrum for the aromatic protons in N4-(40-
fluorophenyl)succinamic acid, which were previously reported
simply as two sets of multiplets [5], and as chemical shifts with no
coupling constants [6]. We also synthesized N4-(40-fluorophenyl)-
3,3-difluorosuccinamic acid (3) and report its spectrum. The
1
1
solvent primarily used for the H NMR analysis of N4-(40-
substituted phenyl)succinamic acids has been Me2SO-d6 [7]. But,
there is a partial overlap of the residual solvent signal with the
signals for the ethylene protons (H2, H3) in several of these
molecules. Thus, acetone-d6 was used as the solvent for this study
(but, see Section 3.2). We have retained the original nuclear spin
pattern designation in order to simplify the discussion.
2. Materials and methods
4-Fluoroaniline and 2,2-difluorosuccinic acid were purchased
from Alfa Aesar, and trifluoroacetic anhydride was purchased from
Oakwood Products; the three chemicals were used without further
purification. Acetone-d6 (99.9 atom % 2H), CDCl3 (99.9 atom % 2H),
and Me2SO-d6 (99.9 atom % 2H) were purchased from Cambridge
Isotopes. All other chemicals were at least ACS grade. 1H NMR
* Corresponding author. Tel.: +1 704 687 4844; fax: +1 704 687 3151.
E-mail address: jmrisley@uncc.edu (J.M. Risley).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.02.003

270
J.M. Risley et al. / Journal of Fluorine Chemistry 132 (2011) 269–275
spectra were recorded on a JEOL ECX-300 NMR spectrometer
operating at 300.53 MHz in a 5 mm probe at ambient temperature
with a 6015 Hz sweep width, 908 pulse angle, and a 65.5k data
block; no line-broadening factor was applied to the accumulated
FID. Natural abundance 13C NMR spectra were recorded: (1) on a
JEOL ECX-300 NMR spectrometer operating at 75.57 MHz in a
5 mm probe at ambient temperature with a 23674 Hz sweep width,
308 pulse angle, and a 32k data block; protons were broad-band
decoupled and a line-broadening factor of 2.0 Hz was applied to the
accumulated FID, or (2) on a JEOL ECA-500 NMR spectrometer
operating at 125.77 MHz in a 5 mm probe at ambient temperature
with a 39308 Hz sweep width, 308 pulse angle, and a 65k data
block; protons were broad-band decoupled and a line-broadening
factor of 2.0 Hz was applied to the accumulated FID. 19F NMR
spectra were recorded on a JEOL ECX-300 NMR spectrometer
operating at 282.78 MHz in a 5 mm probe at ambient temperature
with an 85034 Hz sweep width, 458 pulse angle, and a 131k, 262k,
or 524k data block; no line-broadening factor was applied to the
accumulated FID. The errors in the measured chemical shifts were
ꢀ0.0003 ppm for 1H NMR, ꢀ0.010 or ꢀ0.004 ppm for 13C NMR, and
ꢀ0.002, ꢀ0.001, or ꢀ0.0006 ppm for 19F NMR; J values are given in Hz
B
A
F
NHCOCH2CH2CO2H
B'
2
A'
2.2. N4-(40-Fluorophenyl)-3,3-difluorosuccinamic acid (3)
2,2-Difluorosuccinic acid (0.100 g, 0.00065 mol) was added to
isopropyl acetate (1 mL) [11]. Trifluoroacetic anhydride (0.164 g,
0.108 mL, 0.00078 mol) was added in one portion at room tempera-
ture and the mixture was stirred at 60 8C for 2 h to give 2,2-
difluorosuccinic anhydride (quantitative) [1H NMR (300.52 MHz,
CDCl3):
d d
3.38 (2H, t, JHF = 9.6 Hz). 19F NMR (282.78 MHz, CDCl3):
ꢁ105.2 (t, JFH = 9.6 Hz)]. 2,2-Difluorosuccinic anhydride in isopropyl
acetate (1 mL) was cooled to 5 8C. A solution of 4-fluoroaniline
(0.100 g, 0.0009 mol)inisopropylacetate(1 mL)wasaddedslowlyto
theanhydrideandstirredfor5 daysat60 8C.Water(5 mL)wasadded,
followed by a saturated solution of sodium carbonate until the pH
was 8–9. The organic phase was separated. The aqueous phase was
acidified with 5 M HCl to pH 1 and extracted with isopropyl acetate
(2 ꢂ 10 mL). The organic phase was washed with 2 M HCl (10 mL)
and removed under vacuum. A mixture of N4-(40-fluorophenyl)-3,3-
difluorosuccinamic acid (97.5%) and N4-(40-fluorophenyl)-2,2-
difluorosuccinamic acid (2.5%) (determined by 1H NMR and 19F
NMR) formed as purple-white crystals: yield 0.072 g (0.00029 mol,
45%). For this study, no attempt was made to separate the isomers.
NMR parameters for N4-(40-fluorophenyl)-3,3-difluorosuccinamic
and the errors in the measured coupling constants were ꢀ0.09 for 1
H
NMR, ꢀ0.72 or ꢀ0.60 for 13C NMR, and ꢀ0.65, ꢀ0.32, or ꢀ0.16 for 19
F
NMR. Samples were dissolved in acetone-d6, CDCl3, or Me2SO-d6 with
TMS as reference for 1H NMR and 13C NMR, and with fluorotri-
chloromethane as reference for 19F NMR. The 1H NMR and 19F NMR
spectra for the aromatic protons were simulated using WINDNMR-Pro
(DNMR71.EXE) [8]. Another NMR simulation program, available free
of charge, is gNMR [9].
ΝΗ2
acid: 1H NMR (300.52 MHz, acetone-d6):
3 = 14.77 Hz, H-2), 7.025 (2H, BB0 of AA0BB0X, JBB = 3.10 Hz,
JBF = 8.48 Hz, H-30 and H-50), 7.667 (2H, AA0 of AA0BB0X, JAB = 8.70 Hz,
JAA = 2.80 Hz,JAB = 0.30 Hz,JAF = 4.91 Hz,H-20 andH-60),9.806(1H,s,
NH), 11.4 (1H, bs, OH). 13C NMR (125.77 MHz, acetone-d6):
38.842
d
3.254 (2H, A of A2X2, J2,F-
0
A
B
A'
B'
0
0
d
2
2
(t, JC,F = 25.79 Hz, C-2), 115.336 (d, JC,F = 23.54 Hz, C-30 or C-50),
115.523(d, 2JC,F = 23.54 Hz, C-50 or C-30), 115.919(t, 1JC,F = 252.96 Hz,
F
3
C-3), 122.687 (d, JC,F = 4.05 Hz, C-20 or C-60), 122.719 (d,
3JC,F = 4.05 Hz, C-60 or C-20), 133.928 (C-10), 159.756 (d,
1JC,F = 242.02 Hz, C-40), 161.777 (t, 2JC,F = 27.89 Hz, C-4), 167.400 (t,
1
3JC,F = 7.95 Hz, C-1). 19F NMR (282.78 MHz, acetone-d6):
d
ꢁ104.497
3
(X of A2X2, J3,H-2 = 14.70 Hz, F-3), ꢁ118.828 (X of AA0BB0X,
JAF = 4.91 Hz, JBF = 8.48 Hz, F-40). NMR parameters for N4-(40-fluor-
ophenyl)-2,2-difluorosuccinamic acid: 1H NMR (300.52 MHz, ace-
2.1. N4-(40-Fluorophenyl)succinamic acid (2)
4-Fluoroaniline (5.56 mL, 0.05 mol) and succinic anhydride
(5 g, 0.05 mol) were mixed in a flask with benzene:1,4-dioxane
(2:1, 60 mL) and stirred at room temperature for 4 days [7,10].
N4-(40-Fluorophenyl)succinamic acid precipitated as pale, purple
crystals: yield 1.31 g (0.006 mol, 12%); mp 156 8C. 1H NMR
tone-d6): d
3.443 (2H, A of A2X2, J3,F-2 = 13.40 Hz, H-3), 7.196 (2H, BB0
of AA0BB0X, H-30 and H-50), 7.373 (2H, AA0 of AA0BB0X, H-20 and H-60).
19F NMR (282.78 MHz, acetone-d6):
d
ꢁ107.364 (X of A2X2, JF,H-
3
3 = 13.39 Hz, F-2), ꢁ118.835 (X of AA0BB0X, F-40).
(300.53 MHz, acetone-d6):
d
2.656 (4H, center of AA0BB0, H-2 and
H-3), 7.053 (2H, BB0 of AA0BB0X, JBB = 3.30 Hz, JBF = 8.70 Hz, H-30
B
A
0
and H-50), 7.667 (2H, AA0 of AA0BB0X, JAB = 8.90 Hz, JAA = 2.80 Hz,
0
JAB = 0.30 Hz, JAF = 5.02 Hz, H-20 and H-60), 9.248 (1H, NH), OH
0
F
not observed [lit. [5] (300 MHz, Me2SO-d6):
(2H, m), 7.60 (2H, m), 10.00 (1H, s), 12.00 (1H, s); lit. [6]
(400 MHz, Me2SO-d6):
2.51 (H-2), 2.54 (H-3), 7.12 (H-30 and H-
50), 7.59 (H-20 and H-60), 10.00 (NH), 12.13 (OH)]. 13C NMR
d
2.50 (4H, m), 7.20
NHCOCF2CH2CO2H
d
3
B'
A'
(75.5 MHz, Me2SO-d6):
d 29.309 (C-2), 31.460 (C-3), 115.737
(2JC,F = 21.67 Hz, C-30 and C-50), 121.100 (3JC,F = 7.22 Hz, C-20 and
C-60), 136.225 (C-10), 158.296 (1JC,F = 239.14 Hz, C-40), 170.500
3. Results and discussion
(C-4), 174.344 (C-1) [lit. [6] (100 MHz, Me2SO-d6):
d 29.28 (C-2),
31.42 (C-3), 115.72 (C-30 and C-50), 121.08 (C-20 and C-60), 136.21
(C-10), 158.27 (C-40), 170.48 (C-4), 174.33 (C-1)]. 19F NMR
3.1. 4-Fluoroaniline
(282.78 MHz, Me2SO-d6):
JBF = 8.70 Hz, F-40).
d
ꢁ119.755 (X of AA0BB0X, JAF = 5.02 Hz,
The 1H NMR spectrum at 300 MHz for the aromatic protons and
the 19F NMR spectrum at 283 MHz for the fluoro group of

J.M. Risley et al. / Journal of Fluorine Chemistry 132 (2011) 269–275
271
Fig. 1. (a) 1H NMR spectrum for the aromatic protons of 4-fluoroaniline (1) in acetone-d6 (internal standard TMS) at 300.53 MHz; no line-broadening factor was applied. (b)
19F NMR spectrum for the fluoro group of 4-fluoroaniline (1) in acetone-d6 (internal standard CCl3F) at 282.78 MHz using a 524k data block and 85024 Hz sweep width; no
line-broadening factor was applied. The two NMR spectra form a second-order, AA0BB0X, system.
4-fluoroaniline (1) in acetone-d6 are shown in Fig. 1; the chemical
shift for the protons at 2,6 (A,A0) is at
6.64 ppm and the chemical
shift for the protons at 3,5 (B,B0) is at
6.82 ppm. Using the NMR
several lines for both the A and B protons. This shows that the
analyses by Smith [2] at 60 Hz and by Forchioni and Chachaty [4] at
250 MHz in the presence of a lanthanide shift reagent were
incomplete. Interestingly, in an earlier paper by Ernst and
Mannschreck [12], the NMR spectrum at 60 MHz of 4-fluoroaniline
in CDCl3 in the presence of a lanthanide shift reagent clearly
showed several of the missed lines. The analysis by Dischler [3]
results in a simulation (Fig. 2(c)) that is very close to the observed
spectrum (Fig. 1(a)). The difference between the analyses of
Richard and Schaefer [1] and of Dischler [3] is the value for the
d
d
data for each reported analysis (Table 1) [1–4], the second-order,
AA0BB0X, 1H NMR spectrum at 300 MHz was simulated using
WINDNMR [8], and the results are shown in Fig. 2(a)–(d). There is
broad, general agreement between the four analyses with each
simulation showing four signals for the A and A0 protons and three
signals for the B and B0 protons, but they differ in the details. The
first reported analysis at 29.92 MHz by Richards and Schaefer [1]
results in a simulation (Fig. 2(a)) with too many lines. The absence
0
coupling between the 3 and 5 protons (JBB ); Dischler [3] reported a
of coupling between AA0, AB0, and BB0, i.e., JAA , JAB , and JBB ꢃ 0,
value approximately half that reported by Richards and Schaefer
[1] (Table 1). More recent studies of the values for JAF and JBF in
0
0
0
results in simulated spectra (Fig. 2(b) and (d)) that are missing

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J.M. Risley et al. / Journal of Fluorine Chemistry 132 (2011) 269–275
Table 1
(a)
Coupling constants (Hz) in the 1H NMR spectrum for the aromatic protons.
0
0
0
JBB
JAB
JAA
JAB
JAF
JBF
Reference
4-Fluoroaniline (literature values)
8.2
9
2.5
–
ꢃ0
6.4
–
5.1
5.0
4.7
4.6
8.6
8.1
8.7
8.6
[1]
[2]
[3]
[4]
–
8.7
9.2
2.7
0.3
ꢃ0
3.3
ꢃ0
ꢃ0
4-Fluoroaniline (1) (DvAB = 53.50 Hz)
8.60 2.70 0.30 3.30
N4-(40-Fluorophenyl)succinamic acid (2) (DvAB = 184.68 Hz)
4.62
8.82
This study
8.90
2.80
0.30
3.30
5.02
8.70
This study
N4-(40-Fluorophenyl)-3,3-difluorosuccinamic acid (3) (DvAB = 191.90 Hz)
8.70 2.80 0.30 3.10 4.91 8.48 This study
120
100
80
60
40
Hz
(b)
(c)
(d)
4-fluoroaniline [13], N-substituted 4-fluoroaniline [13], and
derivatives of 4-fluoroaniline, for example, N-arylpyridinium salts
[14] and trimethylammonium salts [14], show that the value of JBF
ꢃ2JAF. Zakrzewska et al. [13] reported values for JAF (4.42 Hz) and
JBF (8.71 Hz) in 4-fluoroaniline in CDCl3 at 500 MHz (no full
analysis of the 1H NMR spectrum was given).
The set of parameters we used as a basis for our analysis of the
AA0BB0X system for 4-fluoroaniline (1) in acetone-d6 was the values
0
0
0
from Dischler [3] for JAB, JAA , JAB , and JBB and the values from
Zakrzewska et al. [13] for JAF and JBF. Our approach was to do
simultaneous simulations of the 1H NMR spectrum and the 19F
NMR spectrum for 1 (Fig. 1) using WINDNMR [8]. The optimized
simulations are shown in Fig. 3(a) for the 1H NMR spectrum at
300 MHz and in Fig. 3(b) for the 19F NMR spectrum at 283 MHz. The
values for the coupling constants obtained from the optimized
simulations are given in Table 1; changes in the values of ꢀ0.05 Hz
resulted in simulations that were not as good. From the 19F NMR
optimized simulation, the value for JAF was 4.62 Hz and the value for
JBF was 8.82 Hz. These values are different from those of Zakrzewska
et al. [13], but we believe that these values are more accurate; we
were able to resolve the signals (Fig. 1(b)) whereas Zakrzewska et al.
[13] did not in their published 19F NMR spectrum, quite possibly due
to the line-broadening factor applied. We used no line-broadening
factor. Using the values of Zakrzewska et al. [13], the simulation of the
19F NMR spectrum was not correct. The values we obtained for JAF and
120
100
80
60
40
Hz
120
100
80
60
40
Hz
0
0
0
JBF restricted the variability in the values for JAB, JAA , JAB and JBB in the
simulation of the 1H NMR spectrum. The values obtained from the
optimized simulation of the 1H NMR spectrum (Fig. 3(a)) are in
agreement with those of Dischler [3] with the exception of JAB that is
slightly smaller. The calculated frequencies and intensities for the 48
lines that make up the simulated 1H NMR spectrum (Fig. 3(a)) are
given in Appendix Table A1. The calculated frequencies and
intensities for the 16 lines that make up the simulated 19F NMR
spectrum (Fig. 3(b)) are given in Appendix Table A2. Of the four
analyses [1–4], the values for the coupling constants reported by
Dischler [3] more closely simulated the 1H NMR spectrum for the
aromatic protons of 4-fluoroaniline in acetone-d6. However, our
optimized values for the second-order, AA0BB0X, NMR spectrum for 4-
fluoroaniline given in Table 1 are a new set of parameters that reflects
the improvements in NMR instrumentation that have been made. A
second-order, AA0BB0X, analysis should be used for 4-fluoroaniline
rather than a first-order analysis [15,16].
120
100
80
60
40
Hz
Fig. 2. Simulations of the 1H NMR spectrum for the aromatic protons of 4-
fluoroaniline (1) at 300 MHz with WINDNMR [8] using the four literature values for
the parameters in Table 1: (a) Richards and Schaefer [1], (b) Smith [2], (c) Dischler
[3], (d) Forchioni and Chachaty [4]. The parameters reported by Dischler give a
simulation that is closest to the NMR spectrum shown in Fig. 1(a).
3.2. N4-(40-Fluorophenyl)succinamic acid
second-order, AA0BB0, spectrum [17], and will be discussed in detail
elsewhere [18]. The 13C NMR spectrum agreed with the chemical
shifts for 2 reported by Lee et al. [6], for the methyl ester of 2 [19],
and for the aromatic carbons in 4-fluoroacetanilide [20–22]. The
coupling constants, JC,F, are consistent with those reported for 4-
fluoroacetanilide [21]; however, we did not observe coupling
between the C10 and F (4JC,F). The 19F NMR chemical shift
N4-(40-Fluorophenyl)succinamic acid (2) was synthesized by
reaction of succinic anhydride with 4-fluoroaniline in a mixture of
benzene and 1,4-dioxane (2:1) [7,10]. The 1H NMR chemical shifts
are consistent with those reported by Lee et al. [6] and by Ashwell
et al. [5]. The 1H NMR spectrum for the ethylene group (H2,H3) is a

J.M. Risley et al. / Journal of Fluorine Chemistry 132 (2011) 269–275
273
(a)
120
100
80
60
40
Hz
(b)
40
35
30
25
20
Hz
15
10
5
0
Fig. 3. (a) Optimized simulation of the 1H NMR spectrum for 4-fluoroaniline (1)
(Fig. 1(a)) using WINDNMR [8]. (b) Optimized simulation of the 19F NMR spectrum
for 4-fluoroaniline (1) (Fig. 1(b)) using WINDNMR [8]. The values obtained for the
six coupling constants from the simultaneous simulations of these two NMR spectra
are given in Table 1 and are a new set of values for the parameters for this second-
order, AA0BB0X, system.
Fig. 4. (a) 1H NMR spectrum for the aromatic protons of N4-(40-
fluorophenyl)succinamic acid (2) in acetone-d6 at 300.53 MHz; no line-
broadening factor was applied. (b) Optimized simulation of the spectrum in (a)
at 300 MHz using WINDNMR [8]. From the simultaneous simulations of the 1H NMR
spectrum shown in (a) and the 19F NMR spectrum (not shown) the values for the six
coupling constants are given in Table 1. The values for the coupling constants
change upon formation of the amide bond.
(ꢁ118.03 ppm) agreed with the reported value for 4-fluoroaceta-
nilide [21].
The 1H NMR spectrum at 300 MHz for the aromatic protons of 2
in acetone-d6 is shown in Fig. 4(a); it is readily apparent this is a
second-order, AA0BB0X, system. Interestingly, formation of the
amide bond results in a mirror image of the spectrum for 4-
The most significant changes occur in the values for JAB (increases),
JAF (increases), and JBF (decreases).
The 1H NMR spectrum for the aromatic protons of 2 at
300 MHz was previously reported simply as two sets of
fluoroaniline. The 20,60 protons shift from
while the 30,50 protons at
6.82 ppm shift to
d
6.64 ppm to
d
7.67 ppm
d
d
7.05 ppm. Similar
observations have been reported for other derivatives of 4-
fluoroaniline, for example, 4-fluoroacetanilide [23,24], N-fluoro-
phenyl-1,8-naphthalimide [25], N-arylpyridinium salts [14], and
trimethylammonium salts [14], as well as 4-fluoroaniline in the
presence of a lanthanide shift reagent [12]. As for 4-fluoroaniline,
simultaneous simulations of the 1H NMR spectrum (Fig. 4(a)) and
19F NMR spectrum (not shown) for 2 were done with WINDNMR
[8] using the new set of parameters for 4-fluoroaniline (Table 1) as
the basis set. The optimized simulation for the 1H NMR spectrum is
shown in Fig. 4(b) and the values obtained for the coupling
constants from the optimized simulations are given in Table 1.
Upon formation of the amide bond, the values for several of the
coupling constants change; this is not surprising as the same
phenomenon occurs in other 40-substituted phenyl anilides [7].
multiplets, a first-order analysis [
2H)] [5], and at 400 MHz as simply chemical shifts [
d
7.20 (m, 2H), 7.60 (m,
7.12 (H-
d
30,50), 7.59 (H-20,60)] [6]. The 1H NMR spectrum for the aromatic
protons of other derivatives of 4-fluoroaniline have been
described by a first-order analysis: methyl N4-(40-fluorophe-
nyl)succinamate [19], 4-fluoroacetanilide [20–24,26–28], N-
fluorophenyl-1,8-naphthalimide [25], 5-N-(N-40-fluorophenyla-
cetamide)-10,20-diphenylporphyrin [29], and N-(4-fluorophe-
nyl)-5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thio-
phenecarboxamide [30]. The 1H NMR spectrum for the aromatic
protons of 2 (Fig. 4(a)) shows that, upon formation of the amide
bond, the spectrum for 40-fluorophenyl group does not change
from
spectrum.
a a first-order
second-order, AA0BB0X, spectrum to

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J.M. Risley et al. / Journal of Fluorine Chemistry 132 (2011) 269–275
shift for the 30,50 protons is
d
7.20 ppm. In N4-(40-fluorophenyl)-
3,3-difluorosuccinamic acid (3), the chemical shift for the 20,60
protons is
7.03 ppm, which are nearly identical to the chemical shifts for the
d
7.67 ppm and the chemical shift for the 30,50 protons is
d
same protons in 2 (above), so the difluoromethylene group
adjacent to the amide bond has no effect on the chemical shifts
for the aromatic protons. The 19F NMR spectrum for the aromatic
fluorine and difluoromethylene group (not shown) also showed
signals for the mixture of products. Only 3 was observed in the 13
C
NMR spectrum due to signal to noise limitations. The chemical
shifts and JC,F coupling constants for the aromatic carbons were
consistent with 2 (above) and with values reported for 4-
fluoroacetanilide [20–22], including the two sets of signals for
C20,60 and C30,50 as reported by Kajihara et al. [20]. Coupling of the
carbons to the fluoro groups was observed for the 4 aliphatic
difluorosuccinamic acid carbons that were consistent with the
values for carbon–fluorine coupling.
As for 4-fluoroaniline, simultaneous simulations of the second-
order, AA0BB0X system in the 1H NMR spectrum (Fig. 5) and 19F
NMR spectrum (not shown) for 3 were done with WINDNMR [8]
using the new set of parameters for 4-fluoroaniline (Table 1) as the
basis set. The values obtained for the coupling constants from the
optimized simulations (not shown) are given in Table 1. As was
true for 2, the values for several of the coupling constants change
upon formation of the amide bond. Importantly, the presence of
the difluoromethylene group affects the magnitudes for the values
for four of the coupling constants compared to 2. It is particularly
interesting that the coupling constants decrease in value. These
results indicate that, in amide derivatives of 4-fluoroaniline from
other fluoro acids, such as tetrafluorosuccinic acid, trifluoroacetic
acid, etc., the fluoro groups affect the magnitudes of the coupling
constants in the AA0BB0X spectrum for the aromatic protons.
1
Fig. 5. H NMR spectrum for the aromatic protons of N4-(40-fluorophenyl)-3,3-
difluorosuccinamic acid (3) in acetone-d6. The signals at 7.20 and 7.37 ppm are
d
signals for the aromatic protons of the small amount (2.5%) of N4-(40-fluorophenyl)-
2,2-difluorosuccinamic acid formed in the reaction of 2,2-difluorosuccinic
anhydride and 4-fluoroaniline, and shows that nucleophilic attack does not
necessarily occur at the more electrophilic carbon. From the simultaneous
simulations of this 1H NMR spectrum and the 19F NMR spectrum (not shown)
the values for the six coupling constants for
3 are given in Table 1. The
difluoromethylene affects the magnitudes of the values for several of the coupling
constants, but does not affect the chemical shifts for the aromatic protons.
Although the solvent primarily used for the 1H NMR analysis of
N4-(40-fluorophenyl)succinamic acid, and N-40-fluorophenyl ani-
lides in general, has been Me2SO-d6, acetone-d6 was the solvent
used in this study because of a partial overlap of the residual
solvent signal in Me2SO-d6 with the signals for the ethylene group
(H2,H3) in several N4-(40-substituted phenyl)succinamic acids [7].
However, we investigated the solvent effect [31] on the 1H NMR
spectrum for the aromatic protons in 2 in Me2SO-d6 (not shown).
The chemical shift for the 20,60 protons was shifted upfield approx.
0.08 ppm (
while the chemical shift for the 30,50 protons was downfield approx.
0.07 ppm ( 7.05 ppm in acetone-d6 to 7.12 ppm in Me2SO-d6).
Switching solvents resulted in small changes in the line spacings
and intensities in the splitting patterns as expected for a second-
order spin system, but the values for the six coupling constants
obtained from the optimized simulations were the same in the two
solvents for the aromatic protons of N4-(40-fluorophenyl)succi-
namic acid.
4. Conclusions
A new set of parameters was obtained for the second-order,
AA0BB0X, NMR spectrum for 4-fluoroaniline by simultaneous
simulation of the 1H and 19F NMR spectra using WINDNMR. The
NMR spectrum for the aromatic protons of 40-fluoroanilides is
second-order, AA0BB0X; simultaneous simulation of the 1H and 19F
NMR spectra gave optimized values for the coupling constants that
change upon formation of a carboxamide bond. The values for the
coupling contants are the same in acetone-d6 and in Me2SO-d6,
although there are small changes in the chemical shifts for the
protons in the two solvents; small changes occur in the line
spacings and intensities in the splitting patterns in the NMR
spectrum as expected for a second-order system.
d 7.67 ppm in acetone-d6 to d 7.59 ppm in Me2SO-d6)
d
d
3.3. N4-(40-Fluorophenyl)-3,3-difluorosuccinamic acid
Acknowledgements
N4-(40-Fluorophenyl)-3,3-difluorosuccinamic acid (3) was syn-
thesized by reaction of 2,2-difluorosuccinic anhydride (prepared
by reaction of 2,2-difluorosuccinic acid with trifluoroacetic
anhydride) with 4-fluoroaniline [11]. It was expected that the
electrophilicity of the carbonyl carbon adjacent to the difluor-
omethylene group would give N4-(40-fluorophenyl)-3,3-difluoro-
succinamic acid as the only product as has been observed for other
reactions [7,11]. However, interestingly, a very small percentage of
N4-(40-fluorophenyl)-2,2-difluorosuccinamic acid (2.5%) was
formed in the reaction as shown in the 1H NMR spectrum for
the aromatic protons (Fig. 5), as well as the methylene protons (not
shown). In N4-(40-fluorophenyl)-2,2-difluorosuccinamic acid, the
The authors thank Prof. John B. Grutzner, Department of
Chemistry, Purdue University, for helpful initial discussions and
comments on the manuscript. Funding was provided, in part, from
the Department of Chemistry, UNC-Charlotte. We thank the NSF
for Grant 0321056.
Appendix A
chemical shift for the 20,60 protons is
d
7.37 ppm and the chemical
See Tables A1 and A2.

J.M. Risley et al. / Journal of Fluorine Chemistry 132 (2011) 269–275
275
Table A1
Table A2
Calculated frequencies and intensities for the optimized simulation of the 1H NMR
spectrum for 4-fluoroaniline at 300.53 MHz using the new set of parameters in
Table 1 (DnAB = 53.50 Hz).
Calculated frequencies and intensities for the optimized simulation of the 19F NMR
spectrum for 4-fluoroaniline at 282.78 MHz using the new set of parameters in
Table 1.
Line
Frequencya
Intensity
Line
Frequencya
Intensity
1
2
121.71
66.40
2.32
2.32
2.32
2.32
1.69
1.69
1.69
1.69
0.78
0.78
0.78
0.78
1.68
1.68
1.68
1.68
0.77
0.77
0.77
0.77
0.31
0.31
0.31
0.31
1.23
1.23
1.23
1.23
2.35
2.35
2.35
2.35
1.45
1.45
1.45
1.45
0.91
0.91
0.91
0.91
0.31
0.31
0.31
0.31
1.43
1.43
1.43
1.43
1
2
34.64
30.00
25.86
25.85
30.00
21.21
21.20
17.06
25.36
21.21
21.21
12.41
16.55
16.57
12.41
7.77
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
3
114.35
122.67
70.00
3
4
4
5
5
6
122.70
59.85
6
7
7
8
113.92
61.76
8
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
57.54
10
11
12
13
14
15
16
65.86
126.31
66.48
116.16
122.08
66.46
105.56
113.88
113.91
65.34
a
The chemical shift (in Hz) from fluorotrichloromethane may be obtained by
adding ꢁ36840.63 Hz to the frequency.
55.21
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53.91
110.22
57.52
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